Research Article: PET imaging of HER2 expression with an 18F-fluoride labeled aptamer

Date Published: January 25, 2019

Publisher: Public Library of Science

Author(s): Hyun Jeong Kim, Jun Young Park, Tae Sup Lee, In Ho Song, Ye Lim Cho, Ju Ri Chae, Hyungu Kang, Jong Hoon Lim, Jung Hwan Lee, Won Jun Kang, Byeong-Cheol Ahn.


Aptamers are oligonucleotide or peptide molecules that bind to a target molecule with high affinity and specificity. The present study aimed to evaluate the target specificity and applicability for in vivo molecular imaging of an aptamer labeled with a radioisotope.

The human epidermal growth factor receptor 2 (HER2/ErbB2) aptamer was radiolabeled with 18F-fluoride. HER2-positive tumor cell uptake of the aptamer was evaluated in comparison to negative controls by flow cytometry and confocal microscopy. Using 18F-labeled HER2-specific aptamer positron emission tomography (PET), in vivo molecular images of BT474 tumor-bearing mice were taken at 60, 90 and 120 minutes after injection.

In flow cytometric analysis, HER2 aptamer showed strong binding to HER2-positive BT474 cells, while binding to HER2-negative MDA-MB231 cells was quite low. Likewise, in confocal microscopic images, the aptamer was bound to HER2-positive breast cancer cells, with minimal binding to HER2-negative cells. In vivo PET molecular imaging of BT474 tumor-bearing mice revealed significant higher uptake of the 18F-labeled HER2 specific aptamer into the tumor compared to the that of HER2-negative cell tumor(p = 0.033). HER2 aptamer was able to preferentially bind to HER2-positive breast cancer cells both in vitro and in vivo, by recognizing HER2 structure on the surface of these cells.

The 18F-labeled aptamer enabled appropriate visualization of HER2 expression by human breast cancer cells. The results suggest that a radiolabeled HER2 aptamer could potentially be applied in the development of treatment strategies or in targeted therapy against HER2-positive breast cancer cells.

Partial Text

Aptamers, from the Latin “aptus,” meaning to fit, and the Greek “meros,” meaning region, are single-stranded oligonucleotides ranging from 20–90 base pairs in length. Usually derived using Systematic Evolution of Ligands by Exponential Enrichment (SELEX) methodologies [1, 2], aptamers bind to a target molecule with high affinity and specificity [3, 4]. Hence, they are regarded as ideal reagents for detecting and measuring expression of their target molecules. Aptamers have several advantages over antibodies, including reduced production costs, ease of synthesis, low toxicity, low immunogenicity, and the fact that they do not require an organism for their production [5]. Accordingly, aptamers are relatively new reagents in the field of theragnosis. Numerous aptamers have been generated against a variety of targets, such as thrombin [6], nucleolin [7], prostate-specific membrane antigen (PSMA) [8], tenascin-C (TNC) [9], and viral proteins [10]. In the therapeutic arena, Pegaptanib, a targeted anti-VEGF (vascular endothelial growth factor) aptamer [11], was approved by the FDA for treatment of macular degeneration. At present, many aptamers are undergoing preclinical and clinical phase evaluation [12], and more trials with diagnostic and therapeutic oligonucleotides are being carried out. Consequently, there is a growing demand for feasible methods with which to evaluate and verify already developed aptamers.

The primary objective of this study was to investigate tumor-specific PET imaging using radiolabeled aptamers. In this study, SH-1194-35, a HER2-targeted DNA aptamer, was successfully PET imaged in vivo. Since its first description in 1990 [1], numerous SELEX methods have been investigated and many novel aptamers have been developed. Among them, we chose HER2-targeted DNA aptamers as candidates for imaging agents. Previous studies have demonstrated the utility of HER2 aptamers in inhibiting tumorigenic growth, both by themselves [19] and by delivering cytotoxic drugs [18]. There are a few reports on the use of aptamers to image HER2-targeted cancer. Recently, an attempt to apply molecular imaging using a 99mTc-labeled aptamer was reported, describing biodistribution data without images [34]. To our knowledge, the present study is the first report of HER2-targeted 18F-labeled PET imaging using specific aptamer. PET images of BT474 tumor-bearing mice showed reliable tumor-to-background ratios, which implies that the aptamer recognized the HER2 target in vivo.




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